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Diabetes. 2014 Oct;63(10):3438-48. doi: 10.2337/db13-1882. Epub 2014 May 8.

ZnT8-reactive T cells are weakly pathogenic in NOD mice but can participate in diabetes under inflammatory conditions.

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  • 1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
  • 2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO unanue@wustl.edu.

Abstract

Autoantibodies to the islet-specific Zn transporter ZnT8 (Slc30a8), as well as CD4 T cells, have been identified in patients with type 1 diabetes. Here we examined for CD4 T-cell reactivity to ZnT8 epitopes in the NOD mouse. Immunization with a cytoplasmic domain of the protein or with peptides predicted to bind to I-A(g7) resulted in a CD4 T-cell response, indicating a lack of deletional tolerance. However, presentation by intraislet antigen-presenting cells (APC) to the T cells was not detectable in prediabetic mice. Presentation by islet APC was found only in islets of mice with active diabetes. In accordance, a culture assay indicated the weak transfer of ZnT8 reactivity from insulinomas or primary β-cells to APC for presentation to T cells. A T cell directed to one peptide (345-359) resulted in the transfer of diabetes, but only in conditions in which the recipient NOD mice or NOD.Rag1(-/-) mice were subjected to light irradiation. In late diabetic NOD mice, CD4 T cells were found as well as a weak antibody response. We conclude that in NOD mice, ZnT8 is a minor diabetogenic antigen that can participate in diabetes in conditions in which the islet is first made receptive to immunological insults.

© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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